Molecular baskets form inclusion complexes with phenethylamine drugs in water.

Molecular basket 16- comprising a nonpolar cavity and an anionic nest of six carboxylates at its rim was found to form inclusion complexes with (1R, 2S)-ephedrine, (1R, 2R)-pseudoephedrine, and (1S, 2R)-tranylcypromine. Experimental results (NMR) and theory (MM/DFT) suggest the basket encapsulates phenethylamines in unique and predictable fashion.

Dynamic and Assembly Characteristics of Deep-Cavity Basket Acting as a Host for Inclusion Complexation of Mitoxantrone in Biotic and Abiotic Systems.

We describe the preparation, dynamic, assembly characteristics of vase-shaped basket 13- along with its ability to form an inclusion complex with anticancer drug mitoxantrone in abiotic and biotic systems. This novel cavitand has a deep nonpolar pocket consisting of three naphthalimide sides fused to a bicyclic platform at the bottom while carrying polar glycines at the top. The results of 1 H Nuclear Magnetic Resonance (NMR), 1 H NMR Chemical Exchange Saturation Transfer (CEST), Calorimetry, Hybrid Replica Exchange Molecular Dynamics (REMD), and Microcrystal Electron Diffraction (MicroED) measurements are in line with 1 forming dimer [12 ]6- , to be in equilibrium with monomers 1(R) 3- (relaxed) and 1(S) 3- (squeezed). Through simultaneous line-shape analysis of 1 H NMR data, kinetic and thermodynamic parameters characterizing these equilibria were quantified. Basket 1(R) 3- includes anticancer drug mitoxantrone (MTO2+ ) in its pocket to give stable binary complex [MTO⊂1]- (Kd =2.1 µM) that can be precipitated in vitro with UV light or pH as stimuli. Both in vitro and in vivo studies showed that the basket is nontoxic, while at a higher proportion with respect to MTO it reduced its cytotoxicity in vitro. With well-characterized internal dynamics and dimerization, the ability to include mitoxantrone, and biocompatibility, the stage is set to develop sequestering agents from deep-cavity baskets.

Crystalline Nanoparticles of Water-Soluble Covalent Basket Cages (CBCs) for Encapsulation of Anticancer Drugs.

We herein describe the preparation, assembly, recognition characteristics, and biocompatibility of novel covalent basket cage CBC-11, composed of four molecular baskets linked to four trivalent aromatic amines through amide groups. The cage is tetrahedral in shape and similar in size to small proteins (Mw =8637 g/mol) with a spacious nonpolar interior for accommodating multiple guests. While 24 carboxylates at the outer surface of CBC-11 render it soluble in aqueous phosphate buffer (PBS) at pH=7.0, the amphiphilic nature prompts its assembly into nanoparticles (d=250 nm, DLS). Cryo-TEM examination of nanoparticles revealed their crystalline nature with wafer-like shapes and hexagonally arranged cages. Nanoparticulate CBC-11 traps anticancer drugs irinotecan and doxorubicin, with each cage binding up to four drug molecules in a non-cooperative manner. The inclusion complexation resulted in nanoparticles growing in size and precipitating. In media containing mammalian cells (HCT 116, human colon carcinoma), the IC50 value of CBC-11 was above 100 µM. While this work presents the first example of a large covalent organic cage operating in water at the physiological pH and forming crystalline nanoparticles, it also demonstrates its biocompatibility and potential to act as a polyvalent binder of drugs for their sequestration or delivery.

Rapid Access to Chiral and Tripodal Cavitands from ß-Pinene.

We report Pd-catalyzed cyclotrimerization of (+)-α-bromoenone, obtained from monoterpene ß-pinene, into an enantiopure cyclotrimer. This C3 symmetric compound has three bicyclo[3.1.1]heptane rings fused to its central benzene with each ring carrying a carbonyl group. The cyclotrimer undergoes diastereoselective threefold alkynylation with the lithium salts of five terminal alkynes (41-63 %, de=4-83 %). The addition enabled a rapid synthesis of a small library of novel chiral cavitands that, in shape, resemble a tripod stand. These molecular tripods include a tris-bicycloannelated benzene head attached to three alkyne legs twisted in one direction to form a nonpolar cavity with polar groups as feet. Tripods with methylpyridinium and methylisoquinolinium legs, respectively, form inclusion complexes with anti-inflammatory and chiral drugs (R)/(S)-ibuprofen and (R)/(S)-naproxen. The mode of binding shows drug molecules docked in the cavity of the host through ion-ion, cation-π, and C-H-π contacts that, in addition of desolvation, give rise to complexes having millimolar to micromolar stability in water. Our findings open the door to creating a myriad of enantiopure tripods with tunable functions that, in the future, might give novel chemosensors, catalysts or sequestering agents.

Closed Aromatic Tubes-Capsularenes.

In this study, we describe a synthetic method for incorporating arenes into closed tubes that we name capsularenes. First, we prepared vase-shaped molecular baskets 4-7. The baskets comprise a benzene base fused to three bicycle[2.2.1]heptane rings that extend into phthalimide (4), naphthalimide (6), and anthraceneimide sides (7), each carrying a dimethoxyethane acetal group. In the presence of catalytic trifluoroacetic acid (TFA), the acetals at top of 4, 6 and 7 change into aliphatic aldehydes followed by their intramolecular cyclization into 1,3,5-trioxane (1 H NMR spectroscopy). Such ring closure is nearly a quantitative process that furnishes differently sized capsularenes 1 (0.7×0.9 nm), 8 (0.7×1.1 nm;) and 9 (0.7×1.4 nm;) characterized by X-Ray crystallography, microcrystal electron diffraction, UV/Vis, fluorescence, cyclic voltammetry, and thermogravimetry. With exceptional rigidity, unique topology, great thermal stability, and perhaps tuneable optoelectronic characteristics, capsularenes hold promise for the construction of novel organic electronic devices.

Dissipative Formation of Covalent Basket Cages.

Living systems use chemical fuels to transiently assemble functional structures. As a step toward constructing abiotic mimics of such structures, we herein describe dissipative formation of covalent basket cage CBC 5 by reversible imine condensation of cup-shaped aldehyde 2 (i.e., basket) with trivalent aromatic amine 4. This nanosized [4+4] cage (V=5 nm3 , Mw =6150 Da) has shape of a truncated tetrahedron with four baskets at its vertices and four aromatic amines forming the faces. Importantly, tris-aldehyde basket 2 and aliphatic tris-amine 7 undergo condensation to give small [1+1] cage 6. The imine metathesis of 6 and aromatic tris-amine 4 into CBC 5 was optimized to bias the equilibrium favouring 6. Addition of tribromoacetic acid (TBA) as a chemical fuel perturbs this equilibrium to result in the transient formation of CBC 5, with subsequent consumption of TBA via decarboxylation driving the system back to the starting state.

A double-decker cage for allosteric encapsulation of ATP.

In this work, we describe the preparation of double-decker cage [1-H6]6+ comprising two binding pockets, each with three ammonium and three amide hydrogen bonding sites. This novel host possesses a high affinity for trapping two molecules of ATP in an allosteric fashion, with both experiments and theory suggesting the synergistic action of charged hydrogen bonds and π-π stacking in the encapsulation.

Picking on Carbonate: Kinetic Selectivity in the Encapsulation of Anions.

Supramolecular hosts bind to inorganic anions at a fast rate and select them in proportion with thermodynamic stability of the corresponding [anion⊂host] complexes, forming in a reversible manner. In this study, we describe the action of hexapodal capsule 1 and its remarkable ability to select anions based on a large span of rates by which they enter this host. The thermodynamic affinity of 1 toward eighteen anions extends over eight orders of magnitude (0

A computational study of competing conformational selection and induced fit in an abiotic system.

Host-guest complexations can be described by two competing mechanisms, conformational selection (CS) and induced fit (IF). In this work, we used a combination of nudged elastic band (NEB), adaptive steered molecular dynamics (ASMD), and density functional theory (DFT, with a correction for dispersion) to study the dynamics of the pathways (IF/CS) by which two conformers of basket B(+) and B(-) interconvert and trap CX4 guests (X = Cl and Br). While the results from NEB/DFT studies disclosed host-guest noncovalent contacts reducing the basket's conformational dynamics, ASMD methodology suggested an associative mechanism for the guest complexation. With theory in excellent agreement with experiments, NEB and ASMD emerge as the methods of choice for studying dynamics of supramolecular systems.

Enantioselective Construction of Modular and Asymmetric Baskets.

The precise positioning of functional groups about the inner space of abiotic hosts is a challenging task and of interest for developing more effective receptors and catalysts akin to those found in nature. To address it, we herein report a synthetic methodology for preparing basket-like cavitands comprised of three different aromatics as side arms with orthogonal esters at the rim for further functionalization. First, enantioenriched A (borochloronorbornene), B (iodobromonorbornene), and C (boronorbornene) building blocks were obtained by stereoselective syntheses. Second, consecutive A-to-B and then AB-to-C Suzuki-Miyaura (SM) couplings were optimized to give enantioenriched ABC cavitand as the principal product. The robust synthetic protocol allowed us to prepare (a) an enantioenriched basket with three benzene sides and each holding either tBu, Et, or Me esters, (b) both enantiomers of a so-called "spiral staircase" basket with benzene, naphthalene, and anthracene groups surrounding the inner space, and (c) a photo-responsive basket bearing one anthracene and two benzene arms.

From Selection to Instruction and Back: Competing Conformational Selection and Induced Fit Pathways in Abiotic Hosts.

Two limiting cases of molecular recognition, induced fit (IF) and conformational selection (CS), play a central role in allosteric regulation of natural systems. The IF paradigm states that a substrate "instructs" the host to change its shape after complexation, while CS asserts that a guest "selects" the optimal fit from an ensemble of preexisting host conformations. With no studies that quantitatively address the interplay of two limiting pathways in abiotic systems, we herein and for the first time describe the way by which twisted capsule M-1, encompassing two conformers M-1(+) and M-1(-), trap CX4 (X=Cl, Br) to give CX4 ⊂M-1(+) and CX4 ⊂M-1(-), with all four states being in thermal equilibrium. With the assistance of 2D EXSY, we found that CBr4 would, at its lower concentrations, bind M-1 via a M-1(+)→M-1(-)→CBr4 ⊂M-1(-) pathway corresponding to conformational selection. For M-1 complexing CCl4 though, data from 2D EXSY measurements and 1D NMR line-shape analysis suggested that lower CCl4 concentrations would favor CS while the IF pathway prevailed at higher proportions of the guest. Since CS and IF are not mutually exclusive, we reason that our work sets the stage for characterizing the dynamics of a wide range of already existing hosts to broaden our fundamental understanding of their action. The objective is to master the way in which encapsulation takes place for designing novel and allosteric sequestering agents, catalysts and chemosensors akin to those found in nature.

Molecular Recognition of Nerve Agents and Their Organophosphorus Surrogates: Toward Supramolecular Scavengers and Catalysts.

Nerve agents are tetrahedral organophosphorus compounds (OPs) that were developed in the last century to irreversibly inhibit acetylcholinesterase (AChE) and therefore impede neurological signaling in living organisms. Exposure to OPs leads to a rapid development of symptoms from excessive salivation, nasal congestion and chest pain to convulsion and asphyxiation which if left untreated may lead to death. These potent toxins are prepared on a large scale from inexpensive staring materials, making it feasible for terrorist groups or states to use them against military and civilians. The existing antidotes provide limited protection and are difficult to apply to a large number of affected individuals. While new prophylactics are currently being developed, there is still need for therapeutics capable of both preventing and reversing the effects of OP poisoning. In this review, we describe how the science of molecular recognition can expand the pallet of tools for rapid and safe sequestration of nerve agents.

A Hexapodal Capsule for the Recognition of Anions.

We herein describe the preparation, characterization, and recognition characteristics of novel hexapodal capsule 1 composed of two benzenes joined by six hydrogen bonding (HB) groups to encircle space. This barrel-shaped host was obtained by reversible imine condensation of hexakis-aldehyde 2 and hexakis-amine 3 in the presence of oxyanions or halides acting as templates. Fascinatingly, capsule 1 includes 18 HB donating (Csp2-H and N-H) and 12 HB accepting groups (C═O and C═N) surrounding a binding pocket (78 Å3). In this regard, the complexation of fluoride, chloride, carbonate, sulfate, and hydrogen phosphate was probed by NMR spectroscopy (DMSO) and X-ray diffraction analysis to disclose the adaptive nature of 1 undergoing an adjustment of its conformation to complement each anionic guest. Furthermore, the rate by which encapsulated chloride was substituted by sulfate or hydrogen phosphate was slow (>7 days) while the stability of [SO4⊂1]2- was greatest in the series with Ka > 107 M-1 in highly competitive DMSO. With facile access to 1, the stage is set to probe this modular, polyvalent, and novel host to further improve the extraction of tetrahedral oxyanions from waste and the environment or control their chemistry in living systems.

A highly diastereoselective synthesis of deep molecular baskets.

We describe a preparative method for directing Mizoroki-Heck cyclotrimerization of enantioenriched bromonorbornenes into molecular baskets having increasingly deeper and extendable aromatic cavities. Such diastereoselective cyclotrimerizations of the bromo-olefinic substrates resulted from prevalent ß migratory insertions without the formation of palladacycle intermediate(s). The facile access to multigram quantity of a new series of basket-like hosts clears the way for creating novel supramolecular materials for storage, sequestration and catalysis.

A Molecular Capsule with Revolving Doors Partitioning Its Inner Space.

Covalent capsule 1 was designed to include two molecular baskets linked with three mobile pyridines tucked into its inner space. On the basis of both theory (DFT) and experiments (NMR and X-ray crystallography), we found that the pyridine "doors" split the chamber (380 Å3 ) of 1 so that two equally sizeable compartments (190 Å3 ) became joined through a conformationally flexible aromatic barrier. The compartments of such unique host could be populated with CCl4 (88 Å3 ; PC=46 %), CBr4 (106 Å3 ; 56 %) or their combination CCl4 /CBr4 (PC=51 %), with thermodynamic stabilities ΔG° tracking the values of packing coefficients (PC). Halogen (C-X⋅⋅⋅π) and hydrogen bonding (C-H⋅⋅⋅X) contacts held the haloalkane guests in the cavities of 1. The consecutive complexations were found to occur in a negative allosteric manner, which we propose to result from the induced-fit mode of complexation. Newly designed 1 opens a way for probing the effects of inner conformational dynamics on noncovalent interactions, reactivity and intramolecular translation in confined spaces of hollow molecules.

One-Pot Aldol Cascade for the Preparation of Isospiropyrans, Flavylium Salts, and bis-Spiropyrans.

We probed tandem aldol condensations of sixteen o-hydroxyacetophenones, carrying electron-withdrawing and -donating groups at positions 4 and 5, using five molar equivalents of SiCl4 in anhydrous ethanol. Substrates carrying electron-withdrawing groups (EWGs) (0 < ∑σ > 0.63) populated the equilibria with isospiropyrans (12-74% yield), while those carrying electron-donating groups (EDGs) (∑σ < -0.31) gave flavylium salts (50-80%) or thermochromic bis-spiropyrans (73%). The results are of interest for developing novel organic materials possessing switchable photochromic and thermochromic characteristics.

Photoinduced interruption of interannular cooperativity for delivery of cationic guests in water.

The synergy among twelve carboxylates from two hexavalent baskets 16- assisted the encapsulation of one divalent diammonium guest 32+-62+ and the formation of ternary [3-6⊂12]10-. The reduction of basket's multivalency, by photoinduced α-decarboxylation of 16- to give 23-, intercepted the interannular cooperativity operating in the stabilization of capsulpex [3-6⊂12]10- to dramatically diminish the binding affinity towards diammonium guests. As a result, the cationic guests were released into bulk water with 23- assembling into nanoparticles. With numerous drugs carrying positive sites, the finding reported here could now be examined for their light-promoted spatiotemporal delivery.

Tuning the allosteric sequestration of anticancer drugs for developing cooperative nano-antidotes.

A dual-cavity basket 16-, holding six γ-aminobutyric acids at its termini, encapsulates variously sized aromatics 2-7+, including four anthracyclines (8+-11+), driven by the hydrophobic effect and hydrogen bonding (HB). In particular, the formation of stable (K = 1012 M-2) anthracycline complexes [(8+-11+)2⊂16-], assembled into nanoparticles, occurred with positive homotropic cooperativity (α = 4K2/K1 = 1.1 ± 0.3 × 102-1.3 ± 0.7 × 103) in PBS medium. Importantly, weakening the first binding event (K1, i.e. by removing HBs) turned the second one (K2) more favorable. The finding is of interest for developing cooperative nano-antidotes acting as biodetoxifying agents.

Twist-Turn-Twist Motif Chaperoned Inside Molecular Baskets.

Two molecular baskets 16-, each with three (S)-glutamic acids at its rim, were found (NMR, ITC) to complex diammonium alkanes 22+-52+ (+H3N(CH2)nNH3+, n = 7-10) giving ternary [2-5⊂12]10- assemblies (K = 107-109 M-2). From the magnetic perturbation of proton nuclei (1H NMR, NICS), we deduced that each guest assumed a U shape within the binary complex, [2-5⊂1]4-. Two ammonium groups were bound in the "anionic nest" at the top of 16-, while the hydrocarbon chain resided in its nonpolar cavity. From detailed ITC analyses, we showed that the binary complex [2-5⊂1]4- forms first and then another 16- capped [2-5⊂1]4- to give [2-5⊂12]10-, via interactions of the carboxylates at the rims with ammoniums on the guest. Long-range NOEs revealed that U-shaped 22+ and 52+ coiled into highly strained twist-turn-twist formations, for the first time observed within an abiotic host while curiously resembling helix-turn-helix motif found in DNA binding proteins.

An easily accessible isospiropyran switch.

In the presence of SiCl4, three molecules of 5'-bromo-2'-hydroxyacetophenone underwent an unexpected tandem aldol condensation to give a novel isospiropyran switch (69%), with X-ray crystallography confirming its structure. The strong Brønsted acid CH3SO3H turned the colorless isospiropyran into its protonated and open form possessing red color. This process was reversed using the Et3N base, with the acid/base toggling repeatable for at least six times (UV-Vis). When printed on a silica plate, however, the isospiropyran formed a blue-colored product due to, as posited, its stabilization by hydrogen bonding (HB) to silica. An exposure to HB-competing ethyl acetate temporarily "erased" the print only to be brought back by subjecting the plate to a higher temperature for evaporating the solvent. The isospiropyran described here is an easily accessible, chromic, modular and switchable compound that one can incorporate into dynamic materials or use for building chemosensors, molecular machines and organic electronic devices.